This is an application for a residential pilot trial to evaluate the effect of zonisamide (ZNS) on cocaine reinforcement, craving and relapse. Cocaine addiction remains a major social and medical problem that imposes a significant burden on our society, as more than a half million cocaine dependent individuals are seeking treatment every year. Medications that act to antagonize the glutamate system and/or increase the GABA-system are new targets in the search towards effective cocaine treatment. ZNS is part of a new line of antiepileptic agents that act both as glutamate antagonists and to enhance the GABA system. Topiramate, a similar agent, showed a positive signal in a pilot trial for cocaine dependence. ZNS has the advantages of a longer half-life requiring only once a day dosing and, being better tolerated, it requires a shorter induction phase and can be administered at higher doses. We hypothesize that ZNS in moderate to high doses will attenuate the central effect of cocaine and improve the neural perturbations resulting from cocaine use, thus decreasing cocaine craving. Healthy, adult cocaine dependent volunteers (N=25, 15 completers) will be enrolled on our residential unit for 44 days for this double-blind within subject dose-ranging study. Following a short wash-out period, subjects will start ingesting capsules containing either placebo (week 1) or ZNS (week 2-3: 300mg;week 4-5: 600 mg). For validity check, a small group (1:4) will be randomized to receive placebo capsules throughout the study. Cocaine challenge sessions will be conducted 4 times a week on week 1, 3 and 5 (ZNS 0 mg, 300 mg, 600 mg). The pharmacodynamic interactions between ZNS and cocaine will be measured in cocaine dose-response sessions, as well as in a cocaine self-administration procedure offering alternative reinforcers with monetary values. Cocaine reinforcing effect will be evaluated over a range of doses relevant to those used illicitly, and subjective and objective outcome on mood and behaviors will be collected. In addition, because topiramate appears to reduce smoking, the effect of zonisamide on ad-lib smoking will be studied on the days when no other procedure interferes with smoking behaviors. Neurocognitive and psychomotor effects of zonisamide treatment will also be studied with an extensive test battery on the day of the week when no cocaine is administered. This study will explore the potential therapeutic effect of zonisamide for the treatment of cocaine dependence while providing necessary safety measures required to launch an outpatient clinical trial, and will concurrently assess its potential for smoking cessation. PUBLIC HEALTH RELEVANCE: The study will test whether the antiepileptic drug zonisamide will decrease cocaine's reinforcing effect, craving and relapse in chronic stimulant abusers. Chronic stimulant abuse induces changes in the brain resulting in neurotransmitter imbalances [Kalivas, 2007] that could perpetuate the addiction process. Zonisamide's mechanisms of actions could oppose these changes and restore a physiologic balance between the excitatory, inhibitory [Ueda, 2003] and reward [Okada, 1995] brain systems.